Nicotinic acid, derivatives, actions

U-56324 (28), a nicotinic acid derivative, has hypoglycaemic activity in the 18-h fasted normal rat [173] and stimulates in vitro insulin secretion [174]. Study of the in vitro activity in membrane patches from cultured mouse pancreatic jff-cells revealed that it acts directly on ATP-sensitive potassium channels and probably has the same mechanism of action as sulphonylureas [174]. 

Nicotinic acid derivatives - A new type of diuretic molecule, triflocin, promotes the excretion of as much as 30% of filtered sodium in the dog at high doses and, therefore, approaches furosemide and ethacrynic acid in maximum efficacy24, as with the latter drugs, sodium reabsorption was inhibited in the ascending limb of Henle s loop in animals and man but there was little effect at more distal tubular sites24,25. Thus, K+ and excretion increased and urinary acidity was enhanced. Glucose metabolism was not markedly altered. Synthesized derivatives all were of less interest than the parent molecule. 6-Aminonlcotlnamlde also enhances sodium excretion in the rat, apparently by an action on the distal tubule . 

Naphthalimide, methylation of, 255 Naphthols, tautomerism of, 5 Naphtho-r,2, 4,5-selenazoles, 350 Nicotinic acid derivatives, metal catalysts, action on, 183, 186 Nitrones, 84, 88, 92, 99... 

ZoLLNER (1966) has described favorable results from the use of a nicotinic acid derivative ( -pyridyl-carbinol) with prolonged action available in the U.S.A. as Roniacol time-span. With this material only about of the dose of nicotinic acid is required for the desired effect on plasma cholesterol level, and the occurrence of side effects is substantially decreased. 

Nicotinic acid is also a potent vasodilator, probably by a direct action on smooth muscle cells. It produces cutaneous vasodilatation, itching of the skin, facial flushing, a sensation of feeling hot, pounding in the head, gastric irritation, diarrhea, raised transaminases, hyperglycemia, and hyperuricemia. These unpleasant adverse effects limit its acceptability for many patients. Nicotinic acid as such is not used in the treatment of vascular disorders, but some of its derivatives are, albeit with poor evidence of clinical efficacy. 

The term niacin refers to nicotinic acid (pyridine-3-carboxyhc acid), its amide nicotinamide, and derivatives that show the same biological activity as nicotinamide. A distinction between the two primary vitamin forms has to be considered, however, when considering some aspects of their metabolism and especially their different pharmacological actions at high doses. Structures of both vitamers and the two coenzyme forms containing the nicotinamide moiety are given in Figure 30-23. 

Nicotinic acid exerts a variety of effects on lipoprotein metabolism (7,16,49). One of its most important actions is the inhibition of lipolysis in adipose tissue. This initial inhibition, like those of previously discussed antihyperlipidemic agents, produces a sequence of events that ultimately result in the lowering of plasma triglycerides and cholesterol. Impaired lipolysis decreases the mobilization of free fatty acids, thus reducing their plasma levels and their delivery to the liver. In turn, this decreases hepatic triglyceride synthesis and results in a decreased production of VLDL. Enhanced clearance of VLDL through stimulation of lipoprotein lipase also has been proposed to contribute to the reduction of plasma VLDL levels. Because LDL is derived from VLDL (Fig. 30.5), the decreased production of VLDL ultimately leads to a decrease in LDL levels. The sequential nature of this process has been clinically demonstrated. The reduction in triglyceride levels occurs within several hours after ... 

Ribose phosphates phosphorylated derivatives of ribose. Ribose is phosphorylated in position 5 by the action of ribokinase (EC 2.7.1.15) and ATP ribose 5-phosphate is also produced in the Pentose phosphate cycle (see), and in the Calvin c cle (see) of photosynthesis. Phosphoribomutase cat yses the interconversion of ribose 5-phospbate and ribose 1-phosphate, and the cosubstrate of this reaction is ribose l,5-f>isphosphate. 5-Phosphoribosyl 1-pyrophos-phate donates a ribose 5-phosphate moiety in the de novo biosynthesis of purine and pyrimidine nucleotides (see Purine biosynthesis. Pyrimidine biosynthesis), in the Salvage pathway (see) of purine and pyrimidine utilization, in the biosynthesis of L-Histi-dine (see) and L-Tryptophan (see) and in the conversion of nicotinic acid into nicotinic acid ribotide (see Pyridine nucleotide cycle). Ribose 1-phosphate can also take part in nucleotide synthesis (see Salvage pathway). 

It thus appeared that the action of pyridine-3-sulfonie acid was localized at a reaction converting nicotinic acid to its amide, or at a similar stage of amide formation in a higher derivative. From this point of view, the action of cozymase as an antagonist to pyridine-3-sulfonic acid was unexpected, for the compound was less effective as antagonist than either the acid or amide but analogous phenomena have been discussed on page 417. 

The action of anabasine is similar to that of nicotine. When the piperidine ring of anabasine is opened to produce 8-amino-8-3-pyridyl-n-valeric acid the activity is reduced, and this is also true of the corresponding lactam and the benzoyl derivative. According to De Eds myosmine is less toxic than nicotine but more active on isolated guinea-pig intestine. ... 

Reaction of -picoline over degassed Raney nickel was found to give 5,5 -dimethyl-2,2 -bipyridine (5), the structure of which was established by its synthesis from 2-bromo-5-methylpyridine. Oxidation of this dimethyl-2,2 -bipyridine, and similar oxidation of the diethyl-2,2 -bipyridine derived from 3-ethylpyridinc, gave the corresponding dicarboxylic acid and the same acid was produced by the action of degassed Raney nickel on sodium nicotinate (in water) or on ethyl nicotinate. These transformations established the 5,5 -substitution pattern for three 2,2 -bipyridines derived from 3-substituted pyridines but such evidence is not available for the biaryls... 

Conversion of the derived methyl coumalate into methyl 6-hydroxy-nicotinate (Expt 8.35) is effected by the action of concentrated aqueous ammonia subsequent hydrolysis with aqueous alkali yields 6-hydroxynicotinic acid. 

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